Rationale. The hypothesis that hypoactivity of the NMDA receptor on GABAergic interneurons possibly mediated by reduced activity of glutamate carboxypeptidase II (GCPII) formerly NAALADase) plays a role in the production from symptoms in a subset of patients with schizophrenia is consistent with converging evidence from post-mortem and clinical studies. In addition, we and others have shown that agents which enhance activity at the NMDA receptor complex improve negative symptoms of schizophrenia (for review Goff and Wine, 1997). Accordingly, in this clinical component of the Conte Center, we intend to focus on two primary questions: first, the potential role of glutamatergic function, particularly GCPII activity, in defining a clinically meaningful subtype of patients with schizophrenia and secondly, the identification of predictors and patterns of cortical activation associated with clinical responses to the glycine modulatory site on the NMDA receptor complex partial agonist, D-cycloserine and the full agonist, D-serine. The imaging studies will be carried out in collaboration with Dr. Yurgelun-Todd in Project V and the marker analysis with Drs. Coyle and Tsai in Project IV. Specific Aim 1. Measure serum markers for glutamatergic function and GCPII activity including folypoly-gamma-glutamate in 60 schizophrenics with detailed clinical and cognitive evaluations. Specific Aim 2. The 60 patients will undergo a double blind placebo controlled study of D-cycloserine in which response of cognitive, negative and positive symptoms will be determined along with MRS and fMRI analysis at baseline and at week eight. Specific Aim 3. Six patients will participate in a eight-week, placebo controlled, parallel group trial of D-serine added to conventional anti- psychotic (30) or to atypical anti-psychotic (30). Baseline, outcome, metabolic, MRS and fMRI measures in Specific Aim 2 will be ascertained.